Oncology · Medical Literature
Durable responses to triplet immunotherapy targeting TGF-β, PD-L1, and tumor antigen, with an IL-15 receptor superagonist in mismatch repair proficient castration-resistant prostate cancer.
Abstract
Immune checkpoint blockade is minimally active in unselected castration-resistant prostate cancer (CRPC) and does not reproducibly yield durable decreases in prostate-specific antigen (PSA) levels. The Quick Efficacy Seeking Trial was designed to employ a combination of agents to initiate an immune response (with BN-Brachyury vaccine), potentiate that response (with nogapendekin-alfa inbakicept (NAI), an interleukin (IL)-15 receptor superagonist), and reduce or eliminate immunosuppressive entities in the tumor microenvironment (with bintrafusp alfa, a dual inhibitor of programmed death-ligand 1 and transforming growth factor beta). Epacadostat (an indoleamine 2,3-dioxygenase (IDO) inhibitor) was also employed in one cohort to reduce immune suppression induced by IDO's conversion of tryptophan to kynurenine. Patients with CRPC enrolled sequentially to receive vaccine + bintrafusp alfa (Arm 2.1), vaccine + bintrafusp alfa + NAI (Arm 2.2), and vaccine + bintrafusp alfa + NAI + epacadostat (Arm 2.3), with the primary objective to determine response rate. Adverse events in Arms 2.1 and 2.2 were manageable and consistent with the safety profiles of each agent individually, and notable for five individuals developing isolated adrenocorticotropic hormone deficiency. Arm 2.3 was closed early due to skin toxicity. Sustained declines in PSA were seen in 1/13 (8%) patients in Arm 2.1, 7/24 (29%) patients in Arm 2.2, including six with proficient mismatch repair/microsatellite stable tumors, and 0/6 (0%) patients in Arm 2.3. Analyses of peripheral immune profiles provided evidence of a multifaceted antitumor immune response, including IL-15 receptor superagonist NAI-dependent expansion and activation of natural killer cells and CD8+ T cells, increased effector-to-suppressor immune cell ratios, and induction of cytotoxic immune gene programs. NCT03493945.
Clinical relevance
Mismatch repair proficient (MMRp)/microsatellite stable (MSS) castration-resistant prostate cancer (CRPC) represents the vast majority of CRPC cases and has historically been refractory to immune checkpoint blockade, leaving a critical therapeutic gap. This trial addresses whether rational combinatorial immunotherapy—targeting complementary immunosuppressive axes (PD-L1/TGF-β, IDO) while simultaneously priming and amplifying antitumor immunity (tumor-antigen vaccine, IL-15 superagonist)—can overcome the immunologically 'cold' tumor microenvironment of MMRp CRPC. The findings are clinically timely as they provide proof-of-concept that durable PSA responses are achievable even in MMRp/MSS disease, a population currently lacking effective immunotherapeutic options.
Key findings
1. PSA response rate in the doublet arm (vaccine + bintrafusp alfa, Arm 2.1) was 8% (1/13 patients), establishing a low baseline for checkpoint plus vaccine combinations alone in unselected CRPC. 2. Addition of the IL-15 receptor superagonist nogapendekin-alfa inbakicept (NAI) to vaccine + bintrafusp alfa (Arm 2.2) increased the sustained PSA decline rate to 29% (7/24 patients), representing a clinically meaningful improvement over the doublet. 3. Critically, 6 of the 7 PSA responders in Arm 2.2 harbored MMRp/microsatellite stable tumors, demonstrating immunotherapy efficacy in a biomarker-unselected population traditionally considered checkpoint-refractory. 4. The quadruplet arm incorporating epacadostat (IDO inhibitor; Arm 2.3) yielded 0% PSA response (0/6 patients) and was closed early due to unacceptable skin toxicity, indicating no added benefit and increased harm from IDO inhibition in this context. 5. A notable immune-related adverse event signal emerged across Arms 2.1 and 2.2: five patients developed isolated ACTH deficiency, a distinct endocrinopathy warranting prospective monitoring in future trials using this backbone. 6. Peripheral immune profiling demonstrated NAI-driven expansion and activation of NK cells and CD8+ T cells, increased effector-to-suppressor immune cell ratios, and induction of cytotoxic immune gene programs, providing mechanistic correlates for the observed clinical responses.
Practice implications
The triplet combination of BN-Brachyury vaccine + bintrafusp alfa + NAI (Arm 2.2) should be prioritized for further investigation in MMRp/MSS CRPC, as it achieved durable PSA responses in approximately 29% of patients in a population for whom immunotherapy has otherwise been ineffective; future trials should incorporate MMRp/MSS status as an eligibility or stratification criterion. Clinicians using IL-15 superagonist- and PD-L1/TGF-β inhibitor-based regimens should institute baseline and serial ACTH/cortisol monitoring given the observed signal of isolated ACTH deficiency, even in the absence of other pituitary dysfunction. The addition of epacadostat to this backbone is not supported—it conferred no PSA benefit and caused excess cutaneous toxicity leading to early arm closure—and IDO inhibition should be excluded from future iterations of this regimen.